Technical Field
Embodiments of the present invention are generally directed to combination therapies for treatment of cancers associated with mutations in the KRAS gene.
Description of the Related Art
Ras represents a group of closely related monomeric globular proteins of 189 amino acids (21 kDa molecular mass) which are associated with the plasma membrane and which bind either GDP or GTP. Ras acts as a molecular switch. When Ras contains bound GDP, it is in the resting or off position and is “inactive.” In response to exposure of the cell to certain growth promoting stimuli, Ras is induced to exchange its bound GDP for a GTP. With GTP bound, Ras is “switched on” and is able to interact with and activate other proteins (its “downstream targets”). The Ras protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP, thus turning itself into the off state. Switching Ras off requires extrinsic proteins termed GTPase-activating proteins (GAPs) that interact with Ras and greatly accelerate the conversion of GTP to GDP. Any mutation in Ras which affects its ability to interact with GAP or to convert GTP back to GDP will result in a prolonged activation of the protein and consequently a prolonged signal to the cell telling it to continue to grow and divide. Because these signals result in cell growth and division, overactive Ras signaling may ultimately lead to cancer.
Structurally, Ras proteins contain a G domain which is responsible for the enzymatic activity of Ras—the guanine nucleotide binding and the hydrolysis (GTPase reaction). It also contains a C-terminal extension, known as the CAAX box, which may be post-translationally modified and is responsible for targeting the protein to the membrane. The G domain is approximately 21-25 kDa in size and it contains a phosphate binding loop (P-loop). The P-loop represents the pocket where the nucleotides are bound in the protein, and this is the rigid part of the domain with conserved amino acid residues which are essential for nucleotide binding and hydrolysis (Glycine 12, Threonine 26 and Lysine 16). The G domain also contains the so called Switch I (residues 30-40) and Switch II (residues 60-76) regions, both of which are the dynamic parts of the protein which are often represented as the “spring-loaded” mechanism because of their ability to switch between the resting and loaded state. The key interaction is the hydrogen bonds formed by Threonine-35 and glycine-60 with the γ-phosphate of GTP which maintain Switch 1 and Switch 2 regions respectively in their active conformation. After hydrolysis of GTP and release of phosphate, these two relax into the inactive GDP conformation.
The most notable members of the Ras subfamily are HRAS, KRAS and NRAS, mainly for being implicated in many types of cancer. However, there are many other members including DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS and RRAS2.
Mutations in any one of the three main isoforms of RAS (HRAS, NRAS, or KRAS) genes are among the most common events in human tumorigenesis. KRAS mutations occur in more than 20% of all human cancers with the highest levels in pancreatic (˜90%), colorectal (˜40%), and lung (˜35%), with G12C being a common mutation (glycine-12 to cysteine). This translates into more than 150,000 newly diagnosed cases of KRAS driven cancer yearly in the US alone. These patients have no effective treatment options and their chances for long term survival are extremely low.
After many years of failed efforts, the direct targeting of KRAS was long considered to be impossible. More recently an approach targeting a specific KRAS mutation, G12C, which accounts for nearly 50% of KRAS mutant lung cancers, has been reported (Ostrem et al., Nature 2013, 503:548). We have refined this strategy to yield quite potent inhibitors of KRAS G12C function in cells and in vivo. These compounds hold great promise for the treatment of cancers harboring the KRAS G12C mutation.
While KRAS is a critical driver mutation in many types of cancer, its precise role in established tumors is the subject of some debate. KRAS mutated cancer cells show varied degrees of growth inhibition when mutant KRAS is depleted, with some lines showing only modest effects (Singh et al., Cancer Cell 2009, 15:489). Further, even in lines with clear growth dependence on mutant KRAS, depletion of KRAS does not lead to robust induction of cell death or apoptosis (Sunaga et al., Mol Cancer Ther 2011, 10:336; Young et al., Cancer Discov 2013, 3:112). Thus, despite the central role for mutant KRAS in tumorigenesis, it is possible that inhibition of KRAS alone may not be sufficient for a desirable clinical outcome.
Accordingly, while progress has been made in this field, there remains a need in the art for improved methods for treatment of KRAS mutant cancers, for example combination therapies. The present invention fulfills this need and provides further related advantages.